O riginal Paper European Neurology Hur Neurol 1997:37:186-189 Received: December 11. 1995 Accepted: October 11,1996 Prolongation of QTc Interval in Patients with Parkinson's Disease Hisayoshi Oka Soichiro Mochio Hironori Sato Ko Katayama Internal Medicine (III), Jikei University School of Medicine. Minato-ku, Tokyo, Japan Key W ords Abstract QTc interval Parkinson’s disease Autonomic dysfunction Valsalva maneuver Baroreceptor reflex QTc intervals were measured in 30 patients with Parkinson’s disease and 30 healthy control subjects. The mean value of QTc intervals in patients with Parkinson’s disease significantly exceeded that of healthy controls (418 ± 14 ms vs. 403 ± 18 ms). Prolongation of the QTc interval was unrelated to the administration of levodopa. The mean QTc interval in patients whose Hoehn and Yahr score was III or more was significantly greater than that of patients whose score was II or less (424 ± 12 ms vs. 410 ± 12 ms). A significant corre lation between the QTc interval and the Valsalva ratio, as well as the over shoot, was identified. The QTc interval is closely related to autonomic ner vous system dysfunction, including abnormal baroreceptor reflex function, in patients with Parkinson’s disease. Autonomic nervous system dysfunction is a common finding in Parkinson's disease. However, it has been reported that severe autonomic dysfunction is actually quite rare in patients with Parkinson’s disease. QT interval prolongation and shortening on electrocar diography are influenced by the autonomic nervous sys tem [1, 2], However, the QT interval also changes in response to alterations in the R-R interval [3, 4], In order to exclude the influence of the R-R interval on the QT interval, a corrected QT interval (QTc) calculated from Bazett’s formula, (QTc = QT s R-R) , has been widely used. This method has the advantage of simple applica tion. It has been reported that the QTc interval is prolonged in diabetic patients [6-10]. We have also suggested that QTc prolongation shows a significant correlation with KARfiFR IX /* \I \V J C l \ E-Mail email@example.com Fax +4161 306 12 34 http://www.kargcr.ch © 1997 S.Kargcr AG. Basel 0 0 14-3022/97/0373-0186$ 12.00/0 This article is also accessible online at: http://BioMcdNct.com/kargcr cardiac autonomic nervous dysfunction . Therefore, QTc prolongation may be recognized in patients with Par kinson’s disease, which is accompanied by autonomic nervous system dysfunction. In this study, we measured the QTc interval in patients with Parkinson’s disease and investigated its relation to disease duration and severity as well as other autonomic function tests affected by Parkinson’s disease. We have also attempted to clarify the significance of QTc interval prolongation in Parkinson's disease. Subjects and M ethods QTc Interval in Parkinson's Disease The QTc interval was measured in 30 subjects with Parkinson’s disease (15 males, 15 females, mean age ± SD 64.3 ± 12.0 years) and 30 age-matched healthy controls (15 males, 15 females, mean age ± SD 64.3 ± 11.7 years). After the subjects had been lying quietly Hisayoshi Oka. MD. PhD Third Dept, of Internal Medicine Jikei University School of Medicine 3-25-8 Nishi-Shinabashi, Minato-ku Tokyo 105 (Japan) Downloaded by: Vanderbilt University Library 126.96.36.199 - 10/27/2017 3:22:14 PM Introduction Relation to Ollier Autonomic Function Tests In 23 randomly chosen patients with Parkinson’s disease (mean age 56.5 years), we examined the Valsalva ratio, overshoot, cold pres sor test and changes in blood pressure upon standing. The relation ships between these results and the QTc interval were evaluated. The Valsalva maneuver consisted of blowing into a mouthpiece at a pres sure of 40 mm Hg for 15 s. R-R intervals were recorded during and after the maneuver, and the ratio of the longest R-R interval (ob tained shortly after the maneuver) to the shortest R-R interval (ob tained during the maneuver) defined the Valsalva ratio. In addition, systolic blood pressures were obtained during and after the Valsalva maneuver with a continuous blood pressure monitoring system, CBM-2000 (Nihon Colin Co. Ltd.. Tokyo, Japan). The Valsalva overshoot is defined as the difference between the rebound systolicblood pressure following the maneuver and the initial pre-Valsalva blood pressure. The cold pressor test, in which changes in systolic blood pressure are measured while the subject has 1 hand in ice water (4°C). was also performed. Changes in systolic blood pressure before and after 5 min of standing were measured after the subject had been lying at rest for more than 20 min. Orthostatic hypotension was defined as a fall in systolic blood pressure of 30 mm Hg or more upon standing. Statistical Methods The significance of differences was determined by Student’s t test. A p < 0.05 was considered to indicate a statistically significant difference. The relationship between QTc interval and various auto nomic function tests was evaluated by linear regression analysis. Analysis of covariance was employed to evaluate the independent contribution of severity of disease to QTc interval by adjusting the effect of dosage of levodopa. QTc Prolongation in Parkinson’s Disease Valsalva ratio Fig. 1. Relationship between QTc interval and Valsalva ratio in Parkinson’s patients (n = 23, p < 0.05. r = -0.472). Results QTc Interval in Parkinson’s Disease The QTc interval in subjects with Parkinson’s disease (418 ± 14 ms) was significantly (p < 0.001) greater than that in healthy controls (403 ± 18 ms). Relations to the Duration and Severity o f Disease No significant differences in the QTc intervals were found between patients whose disease duration was short (less than 5 years; n = 17.419 ± 14 ms) versus those with long disease duration (5 or more years; n = 13, 417 ± 15 ms). However, the QTc interval in patients with Par kinson’s disease whose Hoehn and Yahr score was III or more (n = 17, 424 ± 12 ms) significantly (p < 0.05) exceeded that of those who had a Hoehn and Yahr of II or less (n = 13, 410 ± 12 ms). Relation to Autonomic Nervous Dysfunction There were no significant correlations between the QTc interval and blood pressure changes either on the cold pressor test or upon standing. However, as shown in figures 1 and 2, there were significant correlations be tween QTc intervals and the Valsalva ratio, as well as the Valsalva overshoot. Relation to Levodopa Administration There were no significant differences in the QTc inter val of Parkinson’s patients taking levodopa versus those Eur Neurol 1997;37:186-189 187 Downloaded by: Vanderbilt University Library 188.8.131.52 - 10/27/2017 3:22:14 PM for more than 10 min. the QTc interval was measured using an FCP2201 ECG recorder (Fukuda-Denshi Co. Ltd., Tokyo. Japan). The QTe interval was calculated from Bazett's formula. The R-R interval was obtained from 10 measurements in the lead yielding the longest QT interval. The QT interval was measured from the beginning of the Q-wave to the point at which the T-wave became isoelectric. All subjects w»ere examined before lunch. Among the subjects showing no ischemic change on the ECG. those who were found to have elec trolyte imbalances, or were on antiarrhythmic or a- and |)-blocker medications were excluded from this study. The duration of Parkinson’s disease ranged from 1 to 12 years, with a mean of 4.4 years. Subjects consisted of 1 patient with Hoehn and Yahr I. 12 with II. 13 with III and 4 with IV. Hoehn and Yahr stages were evaluated in the on state. Eight patients were not taking medications. Eleven patients were being treated with levodopa (100— 300 mg) in combination with carbidopa. The remaining patients were on levodopa (400-600 mg) in combination with carbidopa. Patients on other anti-Parkinson’s drugs were excluded from this study. All patients met the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for idiopathic Parkinson’s disease [ 12]. Patients with multiple system atrophy, such as Shy-Dragcr syn drome and olivopontocerebellar atrophy, were also excluded accord ing to the criteria of Quinn [ 13). The healthy controls were chosen from among subjects screened in an annual health check-up. None had hypertension or abnormal ECG, were on medication, or had other medically significant find ings. Informed consent was obtained from all study participants. 40-1 30- — 10 -*---- " 1 ------ 1-------------1-------------1------------- 1------------- -------------1 380 400 420 440 460 480 Q T c interval ms F ig . 2 . Relationship between QTc interval and Valsalva over shoot in Parkinson's patients (n = 23, p < 0.05, r = -0.445). not taking levodopa (418 ± 15 ms) or between those on different dosages of levodopa (100-300 mg: 420 ± 8 ms; 400-600 mg: 416 ± 11 ms). After adjusting for the dosage of levodopa by analysis of covariance, Hoehn and Yahr score was still a significant contributor to QTc interval (p = 0.041). D isc u ssio n It has been reported that the QT interval is shortened by stimulating sympathetic function  and prolonged by reducing sympathetic function , Although these studies point to a predominantly sympathetic influence [15-17], parasympathetic nervous function has also been implicated as a modulator of QT duration . However, since the QT interval may be changed by the preceding R-R interval, it is important to exclude the influence of the R-R interval when using the QT interval as a parame ter of autonomic nervous function [3-5, 18]. Correction of the QT interval (QTc interval) by Bazett’s formula is the most widely utilized means of evaluating QT prolon gation , However, the QTc interval may still be in fluenced by the R-R interval in the setting of tachycardia or bradycardia . Parasympathetic tone predominates 188 F.ur Neurol 1997;37:186-189 Oka/Mochio/Sato/Katayama Downloaded by: Vanderbilt University Library 184.108.40.206 - 10/27/2017 3:22:14 PM Valsalva o ve rsh oo t m m Hg over sympathetic tone in the sinus node at rest . The R-R interval is shortened when parasympathetic nervous system function is decreased. The QTc interval is pro longed since it is corrected by dividing by , R-R. The QTc interval appears to be prolonged not only by sympa thetic but also by parasympathetic nervous system dys function. QTc prolongation has been reported in diabetic pa tients. We have suggested that the QTc interval correlates with the Valsalva ratio as well as the overshoot, but not with blood pressure elevation on the cold pressor test, in diabetic patients. We have also observed QTc prolonga tion to be associated with the results of spectral analysis of the R-R interval and to show a significant correlation with cardiac autonomic but not vasomotor nervous function. In this study, QTc intervals correlated significantly with both the Valsalva ratio as well as the Valsalva over shoot in patients with Parkinson's disease. The Valsalva ratio reflects sympathetic in addition to parasympathetic function, because reflex bradycardia occurs in response to vagal activity following a blood pressure overshoot. The Valsalva overshoot reflects sympathetic nervous system function because sympathetic activity, which manifests as tachycardia and peripheral vasoconstriction, stimulates baroreceptors when the arterial pulse pressure drops. Therefore, the QTc interval is considered to be closely related to parasympathetic and sympathetic nervous sys tem function, including the baroreceptor reflex, in Parkin son’s disease. We also found that prolongation of the QTc interval was related to disease severity, as assessed by the Hoehn and Yahr score, but not to disease duration. Orskov et al.  reported that sympathetic nervous dysfunction corre lated with disease duration in Parkinson’s patients. How ever, their patients were not receiving levodopa treat ment. Eight patients in our study were not being treated with levodopa, 11 cases were on low doses (100-300 mg), and 11 cases were on high doses (400-600 mg) of levodo pa. It is known that levodopa-treated patients with Par kinson’s disease have symptoms of sympathetic nervous dysfunction, including orthostatic hypotension [21, 22], Therefore, prolongation of the QTc interval, an indicator of autonomic dysfunction including sympathetic nervous dysfunction, must be taken into consideration as a possi ble effect of levodopa treatment. However, no significant differences in the QTc interval were recognized between subjects taking versus those not taking levodopa, or be tween subjects with different dosages. These findings indicate that QTc prolongation is unrelated to the admin istration of levodopa. It is well known that the dorsal nucleus of vagus is involved in Parkinson’s disease. Dis turbance of the dorsal nucleus of vagus induces cardiac parasympathetic dysfunction. As mentioned above, the QTc interval is prolonged in the setting of parasympathet ic dysfunction. 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